Tumor Progression and Oncogene Addiction in a PDGF-B-Induced Model of Gliomagenesis
Tumor Progression and Oncogene Addiction in a PDGF-B-Induced Model of Gliomagenesis
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DOI：
10.1593/neo.08814
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发表时间：
2008-12-01
期刊：
影响因子：
4.8
通讯作者：
Malatesta, Paolo
中科院分区：
文献类型：
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作者：
Calzolari, Filippo;Appolloni, Irene;Malatesta, Paolo
血小板衍生生长因子B（PDGF-B）过表达诱导小鼠胚胎神经祖细胞发生不同级别的胶质瘤。我们首次正式证明了PDGF-B诱导的肿瘤经历了从非致瘤性低级别肿瘤向高度恶性形式的进展。这一结果表明，单独的PDGF-B信号传导不足以赋予细胞恶性，需要在这一过程中进一步的分子损伤。我们的研究结果表明，这些病变之一是由肿瘤抑制基因Btg 2的下调。通过体内移植试验，我们进一步证明了完全进展的肿瘤是PDGF-B成瘾的，因为当PDGF-B转基因沉默时，它们的肿瘤增殖能力丧失，而在其重新激活后，它会迅速重新获得。我们提供的证据表明，这种癌基因成瘾不是由于需要PDGF-B作为有丝分裂原，而是由于需要PDGF-B克服细胞-细胞接触抑制并赋予肿瘤细胞体内浸润潜力。
Platelet-derived growth factor B (PDGF-B) overexpression induces gliomas of different grades from murine embryonic neural progenitors. For the first time, we formally demonstrated that PDGF-B-induced neoplasms undergo progression from nontumorigenic low-grade tumors toward highly malignant forms. This result, showing that PDGF-B signaling alone is insufficient to confer malignancy to cells, entails the requirement for further molecular lesions in this process. Our results indicate that one of these lesions is represented by the down-regulation of the oncosuppressor Btg2. By in vivo transplantation assays, we further demonstrate that fully progressed tumors are PDGF-B addicted because their tumor-propagating ability is lost when the PDGF-B transgene is silenced, whereas it is promptly reacquired after its reactivation. We provide evidence that this oncogene addiction is not caused by the need for PDGF-B as a mitogen but, rather, to the fact that PDGF-B is required to overcome cell-cell contact inhibition and to confer in vivo infiltrating potential on tumor cells.